Pharmaceutical formulations containing dopamine receptor ligands

Abstract

The present invention relates to stable and bioavailable immediate release formulations comprising dopamine receptor ligands. Methods of treating various disorders by administering the formulations are also described.

We claim: 
     
       1. A method of treating a condition selected from the group consisting of schizophrenia, bipolar disorder, acute mania, and depression, the method comprising administering to a patient in need thereof a solid oral pharmaceutical formulation comprising from about 0.05 to about 9 mg trans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea, or a pharmaceutically acceptable salt thereof, and an excipient having low water activity selected from the group consisting of pregelatinized starch, mannitol, anhydrous calcium hydrogen phosphate, and mixtures thereof, wherein the formulation provides an in vivo plasma profile comprising a mean C max  of less than about 26.3 ng/mL, a mean AUC 0 -∞ of more than about 2 ng·hr/mL and a mean T max  of about 3 or more hours, wherein the formulation has a dissolution rate of more than about 80% within about the first 60 minutes following administration of the composition to the patient; and wherein the formulation has a pH in the range of about 9.0 to about 12.0. 
     
     
       2. The method of  claim 1 , wherein the formulation comprises about 1.5 mg trans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea, or a pharmaceutically acceptable salt thereof, and provides an in vivo plasma profile comprising a mean C max  of less than about 2.7 ng/mL and a mean T max  of about 3 or more hours. 
     
     
       3. The method of  claim 1 , wherein the formulation comprises about 3 mg trans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea, or a pharmaceutically acceptable salt thereof, and provides an in vivo plasma profile comprising a mean C max  of less than about 5.3 ng/mL and a mean T max  of about 3 or more hours. 
     
     
       4. The method of  claim 1 , wherein the formulation comprises about 4.5 mg trans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea, or a pharmaceutically acceptable salt thereof, and provides an in vivo plasma profile comprising a mean C max  of less than about 7.9 ng/mL and a mean T max  of about 3 or more hours. 
     
     
       5. The method of  claim 1 , wherein the formulation comprises about 6 mg trans-I{4-[2-[4-(2,3-dichlorophenyl)-piperazin-I-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea, or a pharmaceutically acceptable salt thereof, and provides an in vivo plasma profile comprising a mean C max  of less than about 10.5 ng/mL and a mean T max  of about 3 or more hours. 
     
     
       6. The method of  claim 1 , wherein the formulation comprises about 9 mg trans-I{4-[2-[4-(2,3-dichlorophenyl)-piperazin-I-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea, or a pharmaceutically acceptable salt thereof, and provides an in vivo plasma profile comprising a mean AUC 0 -∞ of more than about 180 ng·hr/mL and a mean T max  of about 3 or more hours. 
     
     
       7. The method of  claim 1 , wherein the formulation comprises about 0.5 mg trans-I{4-[2-[4-(2,3-dichlorophenyl)-piperazin-I-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea, or a pharmaceutically acceptable salt thereof, and provides an in vivo plasma profile comprising a mean C max  of less than about 0.9 ng/mL and a mean T max  of about 3 or more hours. 
     
     
       8. The method of  claim 1 , wherein the excipient comprises pregelatinized starch. 
     
     
       9. The method of  claim 1 , wherein the excipient comprises mannitol. 
     
     
       10. The method of  claim 1 , wherein the excipient comprises anhydrous calcium hydrogen phosphate. 
     
     
       11. A method of treating a condition selected from the group consisting of schizophrenia, bipolar disorder, acute mania, and depression, the method comprising administering to a patient in need thereof a solid oral pharmaceutical formulation comprising about 1.5 mg, about 3 mg, about 4.5 mg, or about 6 mg, of trans-1 {4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea, or a pharmaceutically acceptable salt thereof, and a pregelatinized starch. 
     
     
       12. The method of claim 11, wherein the solid oral pharmaceutical formulation comprises about 1.5 mg trans-1 {4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea, or a pharmaceutically acceptable salt thereof. 
     
     
       13. The method of claim 11, wherein the solid oral pharmaceutical formulation comprises about 3.0 mg trans-1 {4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea, or a pharmaceutically acceptable salt thereof. 
     
     
       14. The method of claim 11, wherein the solid oral pharmaceutical formulation comprises about 4.5 mg trans-1 {4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea, or a pharmaceutically acceptable salt thereof. 
     
     
       15. The method of claim 11, wherein the solid oral pharmaceutical formulation comprises about 6.0 mg trans-1 {4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea, or a pharmaceutically acceptable salt thereof.